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Adenovirus vaccines and thrombosis
veins could be explained by the non-unidirectional blood flow in these vessels due to the lack of venous valves, with prolonged residence time of the soluble spike pro- tein in this district depending on body posture or when sleeping. The immunological part of this hypothesis is also in agreement with the apparent higher prevalence of VITT in young women, because they have stronger immune reactions than men and older people. To explain the rarity of VITT the authors hypothesized that only some individuals, due to specific major histocompatibili- ty complex combinations, are not able to produce neu- tralizing anti-spike antibodies which would instead pre- vent the binding of soluble spike to endothelial ACE2 and its ominous consequences in most vaccine recipients. This hypothesis was partly validated by the identification through in silico analysis of potential splice sites in the AstraZeneca and Johnson&Johnson codon-optimized spike opening frames and by in vitro studies with HeLa cells showing that vaccine-transduced cells generate tran- scripts smaller than the full spike protein. It would also explain why VITT has not been reported with mRNA vaccines, which release their cargo mRNA directly into the host cells’ cytosol where it is translated into spike protein without undergoing splicing reactions. Finally, it would account for why the incidence of VITT seems to be lower with the Johnson&Johnson vaccine than with the AstraZeneca one, given that the latter carries more splice donor sequences than the former.86
Additional hypotheses on the mechanisms triggering VITT include a genetically determined enhanced expres- sion of FcgRIIa in susceptible subjects, an altered glycosy- lation state of IgG produced in response to vaccination in some individuals making these antibodies more reactive to platelet FcgRIIa,49 the leakage of the Ad vector into the circulation and/or the prior presence of cross-reactive antibodies to other coronaviruses forming immune com- plexes activating platelets.88 However, the hypothesis that VITT develops in subjects with previous, not appar- ent SARS-CoV-2 infection with prior circulating IgG anti- bodies against the spike protein able to activate platelet FcgRIIa89 should be excluded by the observation that most VITT subjects tested for previous or recent COVID-19 infections were negative. Excessive transcription of the spike protein, which would then activate platelets bind- ing to ACE2,90 and vaccine-induced expression of the spike by megakaryocytes and platelets, leading to a thrombo-inflammatory storm,49,91 have also been pro- posed. Another hypothesis starts from the observation that both the ChAdOx1 and the Ad26.CoV2.S vaccines use polysorbate 80 as an excipient. Polysorbate 80 is a non-anionic surfactant that crosses the blood-brain barri- er and enhances microparticle uptake by endothelial cells. Therefore leakage of Ad vector and polysorbate into the circulation and the spike protein produced by vaccination could preferentially localize in brain vessels triggering endothelial activation.92 However, considering that VITT usually develops at least 1 week after vaccination, it is very unlikely that circulating Ad vector or vaccine excipi- ents would still be present in blood, making the alterna-
tive explanations, and in particular an immunological reaction, more likely.
Conclusive remarks
At least two Ad vector-based vaccines against SARS- CoV-2 have been associated with an excess rate of a special form of catastrophic thrombotic syndrome associated with thrombocytopenia of likely autoimmune origin, not observed so far with mRNA-based vaccines, suggesting that the vectors may play a role in eliciting it. Several ele- ments of the Ad vectors and/or of vaccine composition may theoretically interact with platelets, the endothelium and the blood clotting system precipitating this rare com- plication. However, the exact sequence of events leading to the development of this syndrome and, most importantly, the reason why it evolves in only very few subjects with- out apparent predisposing factors remain to be clarified.
It is clear that our understanding of the pathogenesis of VITT is far from complete and that more mechanistic studies are required to clarify it and, it is hoped, to iden- tify risk factors predictive of its development. What is quite likely is that the Ad vector-based vaccine triggers an immunological reaction which, for unknown reasons, in some rare subjects involves especially blood platelets, and possibly some peculiar vascular endothelial districts such as those of the cerebral and splanchnic veins, precipitat- ing the catastrophic vaccine-induced autoimmune throm- bocytopenia thrombosis syndrome. Awareness of this condition and the prompt identification/evaluation of affected patients may lead to successful treatment and recovery (Figure 3).13,84
COVID-19 continues to be a serious global health prob- lem and vaccination against SARS-CoV-2 is the most effective way of limiting illness and death due to the pan- demic. Based on the current available information, and in light of the relative rarity of VITT, the benefits of vacci- nation clearly outweigh the potential risks (https://www.ema.europa.eu/en/documents/dhpc/direct-health- care-professional-communication-dhpc-zolgensma-onasemno- gene-abeparvovec-risk-thrombotic_en.pdf). However, once the global pandemic begins to retreat, the relative impor- tance of even small risks will increase,65 making it critical- ly important to understand the mechanisms leading to this ominous thrombotic syndrome, to identify the prog- nostic factors for its development and to define the best management strategies.13
Disclosures
No conflicts of interest to disclose.
Contributions
PG, VDS, AT, RM, SM and FR wrote the review article.
Acknowledgments
This work was supported in part by grants from Fondazione Cassa di Risparmio di Perugia (#19663 (2020.0508) and FISR 2020 (# 1049) to PG.
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